Chlorite Formulations and Methods of Preparation and Use Thereof

ABSTRACT

Described herein are chlorite formulations having a pH between about 7 and about 8.5, wherein the chlorite formulations are substantially free of deleterious non-chlorite components. Described herein are chlorite formulations, including pharmaceutical formulations, which are formulated for systemic, parenteral, or intravenous administration. Described herein are methods of preparing and methods of using the chlorite formulations described herein.

CROSS-REFERENCE

This application claims priority under 35 USC 120 as a divisionalapplication of U.S. Ser. No. 11/614,859, filed Dec. 21, 2006, whichclaims the benefit under 35 USC 119(e) of US 61/753,497, filed Dec. 22,2005, both of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

The chlorite ion, referred to herein as chlorite, has been used invarious contexts. Sodium chlorite is a strong oxidizing agent, and hasbeen used in water purification, disinfection, and in bleaching anddeodorizing animal products. Because sodium chlorite produces highlytoxic chlorine gas under acid conditions, aqueous solutions employed incommerce are usually provided as extremely basic (approximately pH 13)solutions, with the pH adjusted using sodium hydroxide.

Chlorite has also been used to treat various diseases or conditions. Forexample, chlorite has been used to treat infections and to causeregeneration of bone marrow. See, for example, U.S. Pat. No. 4,725,437and U.S. Pat. No. 4,851,222. Chlorite has also been used to treat HIV,recurrent prostate cancer, cystitis, and chronic active hepatitis Cdisease. See, for example, McGrath et al., Development of WF10, a novelmacrophage-regulating agent, Curr Opin Investig Drugs, 3(3):365-73(March 2002). These diseases or conditions have generally been treatedwith intravenous injection of WF10, a commercially available formulationof chlorite. The approximately 12.3 pH of this formulation may beproblematic for some forms of administration to physiological systems.

Chlorite has also been described for use in treating oral or periodontaldiseases or conditions, such as inflammation of the gingiva. See, forexample, U.S. Pat. No. 6,350,438.

Earlier formulations of chlorite include tetrachlorodecaoxygen, or TCDO,preparations by Kuhne, which are described in greater detail in U.S.Pat. No. 4,507,285 and below; and formulations including inorganicboron, such as those described in U.S. Pat. No. 4,296,103 to Laso;chlorite formulations are also disclosed in, for example, U.S. Pat. No.3,082,146.

TCDO, which is also known as OXO-K993, is one form of stabilizedchlorite. It is available from OxoChemie GmbH (Wanzleben, Germany).OXO-K993 is a mixture of chlorite, chloride, chlorate, and sulfate ions.WF10 is a dilution of TCDO intravenously administered to treat, forexample, HIV/AIDS and cancer. Oxoferin is a more dilute form of OXO-K993which has been used for topical wound healing. All of these formulationscomprise chlorite ion, chloride ion, chlorate ion, and sulfate ion. Forexample, according to the WF10 packaging information, after dilutionWF10 contains 4.25% chlorite ions, 1.9% chloride ions, 1.5% chlorateions, 0.7% sulfate ions, and sodium as the cation (percentages inweight/total volume). The non-chlorite elements of TCDO in these variousforms, for example the chlorate ions, may cause undesirable effects whenadministered to physiological systems. For example, ingestion of sodiumchlorate causes irritation to the gastrointestinal tract, and may resultin nausea, vomiting and diarrhea. Mallinckrodt Baker Inc. MSDS S3314,Aug. 10, 2004. Other symptoms include abdominal pain, hemolysis,methemoglobinemia, cyanosis, anuria, coma, and convulsions. Id. Further,exposure to sodium chlorate may cause liver and kidney damage, andrepeated ingestion of small amounts may cause loss of appetite andweight loss. Id.

Various topically formulated chlorite-containing gums, toothpastes,lozenges, etc., have been developed. See, for example, U.S. Pat. No.6,350,438 and related patents and applications. However, these topical,oral formulations are not appropriate for many uses, including but notlimited to nontopical uses such as parenteral or systemicadministration.

Thus, there remains a need for chlorite formulations that are bettersuited to administration to physiological systems, including but notlimited to parenteral and systemic administration to physiologicalsystems.

SUMMARY OF THE INVENTION

In general, in one aspect the invention provides an aqueous formulationincluding an aqueous solvent, chlorite and a pH-adjusting agent. In someembodiments formulation includes a weight ratio of chlorite:chloratethat is greater than 100:1.5, greater than 100:0.5. In one embodimentthe formulation is substantially free of chlorate.

Some embodiments provide a formulation wherein the weight ratio ofchlorite:sulfate is greater than 100:16.4, or greater than 100:1.6. Inanother embodiment the formulation is substantially free of sulfate.

In another embodiment the formulation includes a weight ratio ofchlorite:chloride that is greater than 100:10.

In certain embodiments the pH of the formulation is between about 7.0and about 11.5, or between about 7.0 and 8.5.

In one embodiment the pH adjusting agent is a phosphate or an acetate.In a particular embodiment the pH adjusting agent is monosodiumphosphate.

In one embodiment the formulation includes a percent by weight ofchlorite that is between about 0.5% and about 5% in the formulation. Inone embodiment the concentration of chlorite in the formulation isbetween about 50 mM and about 100 mM.

In general, in one aspect the invention provides an aqueous formulationincluding chlorite, sodium, phosphate, and water, wherein theformulation has a pH between about 7.0 and about 11.5, and wherein theformulation comprises a weight ratio of chlorite:chlorate of greaterthan 100:0.5. In one embodiment the formulation is comprised essentiallyof chlorite, sodium, phosphate, and water. In one embodiment theconcentration of chlorite is between about 50 mM and about 70 mMchlorite.

In general, in one aspect the invention provides an aqueous formulationincludes chlorite and an aqueous solvent, wherein the formulation showsone or more indicia of a diminished non-specific toxicity relative tothe same concentration of chlorite formulated as WF10 in an in vitroassay.

In general, in one aspect the invention provides an aqueous formulationincluding chlorite and an aqueous solvent, wherein the formulation showsone or more indicia of diminished toxicity when systemicallyadministered to a subject, relative to the toxicity of the sameconcentration of chlorite formulated as WF10, when systemicallyadministered to a subject. In one embodiment the toxicity is one or moreof asthenia, injection site reaction, or injection site pain.

In general, in one aspect the invention provides a pharmaceuticalcomposition including: (a) chlorite;

(b) a pH adjusting agent; and (c) a pharmaceutically acceptableexcipient. In one embodiment the composition has a weight ratio ofchlorite: chlorate of greater than 100:1.5. In a particular embodimentthe excipient includes water.

In general, in one aspect the invention provides a method ofadministering chlorite to a subject, wherein the method includesparenterally administering to a subject in need thereof atherapeutically effective amount of an aqueous formulation comprising anaqueous solvent, a pH adjusting agent and chlorite. In one embodimentthe weight ratio of chlorite:chlorate is greater than 100:1.5. Inanother embodiment the formulation is administered intravenously.

In general, in one aspect the invention provides a unit dose form of aformulation, wherein the unit dose form comprises an effective amount ofa pharmaceutical composition including: (a) chlorite; (b) a pH adjustingagent; and (c) a pharmaceutically acceptable excipient. In oneembodiment the unit dose is ready for administration to a subject. Inanother embodiment the unit dose is diluted prior to administration to asubject. In one embodiment the pH of the composition is between about7.1 and about 7.7.

In general, in one aspect the invention provides a kit including: (a)one or more unit dose forms of claim 26; and (b) one or more ofpackaging and instructions for use to treat one or more diseases orconditions. In one embodiment the kit further includes a diluent in aseparate container from the formulation. In one embodiment theformulation further includes a pharmaceutically acceptable excipient.

In general, in one aspect the invention provides a method of preparing aformulation including chlorite, wherein the method includes: (a)concentrating a chlorite solution at a temperature between 60° C. toabout 100° C., whereby impurities precipitate from the solution; (b)removing the impurities from the concentrated solution by filtration;(c) inducing crystallization of chlorite from the concentrated solutionby freezing; (d) harvesting the resulting chlorite solids by filtration;and (e) dissolving the chlorite solids in an aqueous solvent. In oneembodiment the temperature in step (a) is between 65° C. to about 80° C.In one embodiment the temperature in step (a) is about 70° C. In anotherembodiment the step (a) is carried out under reduced pressure. Inanother embodiment the inducing crystallization of chlorite in step (c)includes cooling the concentrated chlorite solution to a temperature nogreater than about 10° C. In yet another embodiment the concentratedchlorite solution is cooled to a temperature between about 20° C. toabout 30° C. In a particular embodiment the concentrated chloritesolution is cooled to a temperature of 25° C. In one embodiment thefiltration in step (d) is centrifugal filtration. In one embodiment theinvention provides a chlorite composition prepared by the describedmethod.

In general, in one aspect the invention provides a method of preparing aformulation comprising chlorite and an aqueous solvent, wherein themethod includes: (a) adjusting the pH of the formulation to betweenabout 7 and about 11.5 with a pH modifying agent, wherein the pHmodifying agent does not subject the chlorite to high local acidity,wherein the resulting formulation is substantially free of one or moreof a member from the group consisting of chlorate or sulfate ions. Inone embodiment the resulting formulation is substantially free ofchlorate. In another embodiment the formulation is substantially free ofsulfate. In one embodiment the pH is adjusted to about 7.4. In aparticular embodiment the pH modifying agent is monosodium phosphate. Inone embodiment step (a) includes adding the pH adjusting agent to anaqueous mixture of chlorite and aqueous solvent. In one embodiment theinvention provides a chlorite composition prepared by the describedmethod.

In general, in one aspect the invention provides a method of preparing aformulation comprising chlorite, wherein the method includes: (a)adjusting the pH of an aqueous solution comprising chlorite with a pHmodifying agent, and wherein the resulting formulation is substantiallyfree of one or more of chlorate or chlorine dioxide. In one embodimentthe method includes before step (a), the step of purifying the chlorite.In one embodiment the pH is adjusted to between about 7.0 and about11.5. In another embodiment the pH is adjusted to between about 7.0 andabout 8.5. In a particular embodiment the pH is adjusted to about 7.4.In one embodiment the pH modifying agent is monosodium phosphate. In oneembodiment the resulting formulation is substantially free of chlorate.In another embodiment the resulting formulation is substantially free ofchlorine dioxide. In one embodiment step (a) includes adding chlorite oran aqueous mixture thereof to a solution of phosphate buffer. In oneembodiment the phosphate buffer is monosodium phosphate. In a furtherembodiment step (a) comprises adding the pH adjusting agent to anaqueous mixture of chlorite and aqueous solvent.

In a related embodiment purifying comprises the steps of: (a)concentrating a chlorite solution at a temperature between 60° C. toabout 100° C., whereby impurities precipitate from the solution; (b)removing the impurities from the concentrated solution by filtration;(c) inducing crystallization of chlorite from the concentrated solutionby freezing; (d) harvesting the resulting chlorite solids by filtration;and (e) dissolving the chlorite solids in an aqueous solvent. In oneembodiment the temperature in step (a) is between 65° C. to about 80° C.In another embodiment the temperature in step (a) is about 70° C. In oneembodiment the step (a) is carried out under reduced pressure. In oneembodiment inducing crystallization of chlorite in step (c) includescooling the concentrated chlorite solution to a temperature no greaterthan about 10° C. In one embodiment the concentrated chlorite solutionis cooled to a temperature between about 20° C. to about 30° C. toinduce crystallization. In a particular embodiment the concentratedchlorite solution is cooled to a temperature of 25° C. to inducecrystallization. In one embodiment the filtration in step (d) iscentrifugal filtration. In one embodiment the invention provides achlorite composition prepared by the described method.

In general, in one aspect the invention provides a method of treating adisease or disorder comprising administering to a subject in needthereof an effective amount of a pharmaceutical composition including:(a) chlorite; (b) a pH adjusting agent; and (c) a pharmaceuticallyacceptable excipient. In one embodiment the disease or disorder is oneor more of infection, bone marrow degradation, neoplasia, cystitis, HIV,chronic hepatitis C disease, oral disease, periodontal disease,inflammation of the gingiva, topical wounds, multiple sclerosis and aneurodegenerative disease or disorder. In another embodiment the diseaseis a neoplasia selected from one or more of bladder cancer, melanoma,breast cancer, non-Hodgkin's lymphoma, colon and rectal cancer,pancreatic cancer, endometrial cancer, prostate cancer, kidney (renalcell) cancer, skin cancer (non-melanoma), leukemia, thyroid cancer andlung cancer. In one embodiment the disease or disorder is aneurodegenerative disease or disorder. In a particular embodiment theneurodegenerative disease or disorder is a macrophage-associatedneurodegenerative disease or disorder. In one embodiment theneurodegenerative disease or disorder is ALS. In another embodiment theneurodegenerative disease or disorder is Alzheimer's disease. In afurther embodiment the neurodegenerative disease or disorder isParkinson's disease.

In general, in one aspect the invention provides a business methodincluding preparing an item of any of aspects of the invention asdescribed above, according to a GMP protocol.

In general, in one aspect the invention provides a aqueous formulationincluding an aqueous solvent and chlorite, wherein the formulation isproduced using a GMP protocol. In one embodiment the formulation furtherincludes a weight ratio of chlorite:chloride greater than 100:10. Inanother embodiment the ratio of chlorite:chlorate is greater than100:0.5. In another embodiment the chlorite comprises a purity greaterthan 80%, greater than 85%, greater than 90%, greater than 95% orgreater than 99%.In general, in one aspect the invention providesaqueous formulations of chlorite, an aqueous solvent and a pH adjustingagent, as described further herein, as well as pharmaceuticalformulations of the foregoing, kits, methods for making theformulations, and methods for using the formulations, including thepharmaceutical formulations described herein.

Unless the context makes clear, all percentages are weight per totalvolume percentages.

In one aspect are provided aqueous formulations comprising chlorite, anaqueous solvent, and a pH adjusting agent, wherein the formulation has apH of about 7 to about 11.5, and wherein the formulation comprises amember from the group consisting of, or alternatively any one or moreof: no greater than about 1.8% chloride, no greater than about 1.4% ofchlorate, and no greater than about 0.6% sulfate. In some embodimentsare provided aqueous formulations comprising chlorite, an aqueoussolvent and a pH adjusting agent, wherein the formulation has a pH ofabout 7 to about 11.5, and wherein the formulation comprises a memberfrom the group consisting of, or alternatively any one or more of: nogreater than about 0.24% chloride, no greater than about 0.19% ofchlorate, and no greater than about 0.08% sulfate. In some embodimentsare provided aqueous formulations comprising chlorite, an aqueoussolvent and a pH adjusting agent, wherein the formulation has a pH ofabout 7 to about 11.5, wherein the formulation comprises no greater thanabout 85% of the amount of a member of the group consisting of, oralternatively any one or more of chlorate and sulfate when compared toan equal weight/volume percent of chlorite formulated as WF10.

In some embodiments, any of the formulations or pharmaceuticalformulations described herein comprise a pH adjusting agent thatcomprises phosphate. In some embodiments, any of the formulations orpharmaceutical formulations described herein comprises a pH adjustingagent that consists essentially of phosphate. In some embodiments, anyof the formulations or pharmaceutical formulations described hereincomprise a pH adjusting agent that comprises acetic acid. In someembodiments, any of the formulations or pharmaceutical formulationsdescribed herein comprise a pH adjusting agent that consists essentiallyof acetic acid.

In a further aspect are provided methods of administering chlorite to asubject, wherein the method comprises administering a therapeuticallyeffective amount of any of the formulations or pharmaceuticalformulations described herein to a subject in need thereof. In someembodiments, the formulations or pharmaceutical formulations areadministered parenterally. In some embodiments, the formulations orpharmaceutical formulations are administered systemically. In someembodiments, the formulations or pharmaceutical formulations areadministered intravenously. In some embodiments, the formulations orpharmaceutical formulations are administered non-topically.

Described herein are methods of administering chlorite to a subject,wherein the method comprises intravenously administering atherapeutically effective amount of an aqueous pharmaceuticalformulation comprising chlorite, an aqueous solvent, a pH adjustingagent, and a saline solution, wherein the formulation has a pH of about7 to about 11.5, wherein the formulation comprises no greater than about85% of the amount of a member of the group consisting of, oralternatively any one or more of, chlorate and sulfate when compared tothe same percent of chlorite formulated as WF10. In some embodiments,the formulation administered has a pH of about 7.0 to about 10. In someembodiments, the formulation has a pH of about 7.0 to about 9.0. In someembodiments, the formulation administered has a pH of about 7.0 to about8.5. In some embodiments, the formulation administered has a pH of about7.1 to about 7.7. In some embodiments, the method comprisesintravenously administering a therapeutically effective amount of aliquid pharmaceutical formulation comprising chlorite, an aqueoussolvent, saline, and a pH adjusting agent, wherein the formulation has apH of about 7.1 to about 7.7, wherein the formulation comprises nogreater than about 0.6% of sulfate ions or 1.4% of chlorate ions,wherein the concentration of chlorite is between about 2 and about 3 mM.In some embodiments, the method comprises intravenously administering atherapeutically effective amount of a liquid pharmaceutical formulationcomprising chlorite, an aqueous solvent, saline, and a pH adjustingagent, wherein the formulation has a pH of about 7.1 to about 7.7,wherein the formulation comprises no greater than about 0.08% of sulfateions or 0.19% of chlorate ions, wherein the concentration of chlorite isbetween about 2 and about 3 mM.

Described herein are methods of administering chlorite to a subject,wherein the method comprises intravenously administering atherapeutically effective amount of an aqueous pharmaceuticalformulation comprising chlorite, an aqueous solvent, and a salinesolution, wherein the formulation comprises no greater than about 85% ofthe amount of a member of the group consisting of, or alternatively anyone or more of, chlorate and sulfate when compared to the same percentof chlorite formulated as WF10. In some embodiments, the methodcomprises intravenously administering a therapeutically effective amountof a liquid pharmaceutical formulation comprising chlorite, an aqueoussolvent, and saline, wherein the formulation comprises no greater thanabout 0.6% of sulfate ions or 1.4% of chlorate ions, wherein theconcentration of chlorite is between about 2 and about 3 mM. In someembodiments, the method comprises intravenously administering atherapeutically effective amount of a liquid pharmaceutical formulationcomprising chlorite, an aqueous solvent, and saline, wherein theformulation comprises no greater than about 0.08% of sulfate ions or0.19% of chlorate ions, wherein the concentration of chlorite is betweenabout 2 and about 3 mM.

In an additional aspect, provided are methods of treatment comprisingadministering a formulation or pharmaceutical formulation describedherein in a therapeutically effective amount to a subject in needthereof, to treat one or more of the diseases or conditions for whichchlorite is presently used, including but not limited to those diseasesor conditions described herein. In some embodiments, the method oftreatment is to treat one or more of the diseases or conditionsdescribed herein.

In a further aspect are provided use of the formulations orpharmaceutical formulations of chlorite as described herein in themanufacture of a medicament. Particularly, the manufacture of amedicament for use in the treatment of conditions as described herein.Further, the pharmaceutical formulations thereof, variously describedherein, are also intended for use in the manufacture of a medicament foruse in treatment of the conditions and, in accordance with the methods,described herein, unless otherwise noted.

In an additional aspect, provided herein are unit dose forms of aformulation, wherein the unit dose form comprises an effective amount ofany of the formulations or pharmaceutical formulations described herein.

In a further aspect, provided herein are kits comprising one or moreunit dose forms as described herein. In some embodiments, the kitcomprises one or more of packaging and instructions for use to treat oneor more diseases or conditions. In some embodiments, the kit comprises adiluent in a separate compartment from the formulation or pharmaceuticalformulation. In some embodiments, the kit comprises a diluent in aseparate container from the formulation or pharmaceutical formulation.In some embodiments, the kit comprises a diluent which is not inphysical contact with the formulation or pharmaceutical formulation. Insome embodiments, the kit comprises any of one or more unit dose formsdescribed herein in one or more sealed vessels. In some embodiments, thekit comprises any of one or more sterile unit dose forms.

In a further aspect, provided herein are methods of preparing any of theformulations or pharmaceutical formulations described herein.

Described herein are methods of preparing a formulation comprisingchlorite and an aqueous solvent as described herein, wherein step (a)comprises adding chlorite or an aqueous mixture thereof to a solution ofa physiologically compatible buffer. A “physiologically compatible”buffer is a buffer with a level of its constituent components that isgenerally accepted by those of skill in the art as appropriate for usein the subject being treated. In some embodiments, the buffer is aphosphate buffer.

Described herein are methods of preparing a formulation comprisingchlorite and an aqueous solvent as described herein, wherein step (a)comprises adding the pH adjusting agent to an aqueous mixture ofchlorite and an aqueous solvent.

Described herein are methods of preparing a formulation comprisingchlorite as described herein, wherein the resulting formulation issubstantially free of chlorate.

Described herein are methods of preparing a formulation comprisingchlorite as described herein, wherein the resulting formulation issubstantially free of chlorine dioxide.

Unless otherwise noted, it is intended that the formulations, includingthe pharmaceutical formulations, described herein may be used in themethods and kits described herein. As used herein, embodiments describedwith elements “selected from the group consisting of” also contemplatealternative embodiments which are “any one or more of” As used herein,embodiments described as “no greater than” an element, also contemplatealternative embodiments which are “less than about” those elements.Further, aspect and embodiments of the invention described herein alsocontemplate “consisting” and/or “consisting essentially of” aspects andembodiments.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 depicts the relative nonspecific toxicity of a chloriteformulation described in Example 4 versus WF10 in a Jurkat T-cell cellline.

FIG. 2 is a block diagram showing a representative example of a kit.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are chlorite formulations, including but not limited topharmaceutical formulations, better suited to administration tophysiological systems than those previously described, wherein theformulations are suitable for various modes of administration, includingbut not limited to non-topical, parenteral, systemic, or intravenousadministration. In some variations the chlorite formulations describedherein have a pH that is closer to physiological pH than those ofprevious chlorite formulations. In some variations, the chloriteformulations described herein do not have the impurities or deleteriousnon-chlorite elements of previously described chlorite formulations. Insome variations, the chlorite formulations described herein are lesstoxic to physiological systems than those previously described. Alsodescribed herein are methods of treatment of various diseases orconditions described herein. Also described herein is the use of thechlorite formulations and pharmaceutical formulations described hereinin the manufacture of a medicament to treat the diseases or conditionsdescribed herein.

In certain aspects, this invention provides formulation of chlorite inaqueous solution in which the chlorite is 97-99% pure. As used herein,the “purity” of chlorite in a sample is calculated as the percent weightof chlorite salt to the total weight of the sample. In determining thepurity of chlorite in a solution, the weight of the solvent (e.g., waterin an aqueous solution) is not included. Purity may be evaluated usingion chromatography and an ion detector, by calibrated integration of therespective peaks; for example, chlorite, chloride, chlorate, phosphateand sulfate in the compound or formulation. For example, chlorite iscommercially available as sodium chlorite, technical grade, at a purityof 80% (catalog No. 244155 Sigma-Aldrich).

This invention further provides compositions of this invention havereduced amounts of chlorate, sulfate or chloride compared withcommercially available chlorite compositions. As used herein, aformulation is “substantially free” of a molecule if the moleculecomprises no more than 1 part in 1000 per weight of non-solventmolecules in the formulation. In certain embodiments, the weight ratioof chlorite to chlorate is greater than 100:1.5, greater than 100:0.5,greater than 100:1, or greater than 100:0.1. In one embodiment thecomposition is substantially free of chlorate. In another embodiment,the weight ratio of chlorite to chloride greater than 100:45.5 orgreater than 100:8.5. In one embodiment the composition is substantiallyfree of chloride. In a further embodiment, the weight ratio of chloriteto sulfate is greater than 100:16.4 or greater than 100:1.6. In oneembodiment the composition is substantially free of sulfate.

Described herein are methods of adjusting the pH of a chloriteformulation to between about 7 and about 11.5. In some variations, thepH of a chlorite formulation is lowered to between about 7 and about11.5 using a pH adjusting compound that does not expose the formulationto high local acidity. In some variations the pH adjusting compound isany one or more of monosodium phosphate, or acetic acid. Describedherein are methods of adjusting the pH of a chlorite formulation to nogreater than about 11.5.

Also described herein are methods of preparing chlorite formulations andpharmaceutical formulations, including but not limited to the chloriteformulations specifically described herein. Also described herein arekits and methods of administration of the formulations andpharmaceutical formulations described herein. Various exemplary aspectsand variations of the invention are described in the “Brief Summary ofthe Invention,” as well as elsewhere herein, including but not limitedto the Examples. It is also understood that the invention includesembodiments comprising, consisting essentially of, and/or consisting ofone or more elements as described herein.

Formulations

Described herein are aqueous formulations comprising chlorite. In somevariations, the chlorite formulation comprises an aqueous solvent, andoptionally one or more other solvents for chlorite. Described herein areformulations comprising chlorite and an aqueous solvent for chlorite,the formulations having a pH of about 7 to about 11.5.

Solvents or combinations of solvents for use in the formulationsdescribed herein can be determined by a variety of methods known in theart. One nonlimiting example includes (1) theoretically estimatingsolvent solubility parameter value(s) and choosing the one(s) that matchwith chlorite, using standard equations in the field; and (2)experimentally determining the saturation solubility of chlorite in thesolvent(s), and (3) choosing one or more that exhibits the desiredsolubility, and (4) selecting a solvent or solvents that do not diminishthe activity of chlorite, or that do not or only minimally react withchlorite. In some variations, the liquid formulations described hereincomprise a plurality of solvents.

In some variations, the chlorite formulations described herein comprisean aqueous solvent. In some variations, water is the principal solventin the aqueous formulations described herein. In some variations, wateris at least about 50% by volume of the solvent component of an aqueousformulation. In some variations, water is at least about 50% by volumeof the aqueous formulation. In some variations, water is any of betweenabout 50 to about 60, between about 60 to about 70, between about 70 toabout 80, between about 80 to about 90, between about 90 to about 99, atleast about 50, at least about 60, at least about 70, at least about 80,at least about 90, or at least about 95, about 50, about 60, about 70,about 80, about 90, or about 95 percent by volume of the solventcomponent. In some variations, water is any of between about 50 to about60, between about 60 to about 70, between about 70 to about 80, betweenabout 80 to about 90, between about 90 to about 99, at least about 50,at least about 60, at least about 70, at least about 80, at least about90, or at least about 95, percent by volume of the aqueous formulation.In some variations, water is at least about 95% by volume of the aqueousformulation. In some variations, water is between about 80 to about 90%by volume of the aqueous formulation. In some variations, water isbetween about 90 to about 99% by volume of the aqueous formulation.

The formulations may have differing concentration of chlorite. In someembodiments the concentration of chlorite in the formulation is high,and then is diluted to a less concentrated form prior to administration.In some embodiments, a formulation described herein is diluted any ofabout 2.5×, about 5×, about 7.5×, about 10×, about 20×, about 25×, about50×, about 100×, about 200×, about 250×, about 300×, about 500×, orabout 1000×. In some embodiments, a formulation described herein isdiluted about 2.5×, about 5×, about 10×, about 20×, about 25×, about50×, about 100×, about 200×, about 250×, about 300×, about 500×, about1000×; between about 2× and about 10×, between about 10× and about 50×,between about 50× and about 100×, between about 100× and about 500×, orbetween about 500× and about 1000×. In some embodiments, a formulationas described herein is diluted between about 2× and about 10×. In someembodiments, a formulation as described herein is diluted between about10× and about 50×. In some embodiments, a formulation as describedherein is diluted about 7.5×. In some embodiments, a formulation asdescribed herein is diluted about 25×. In some embodiments, aformulation as described herein is diluted about 200×. In somevariations, the concentration of chlorite in the formulations describedherein is between about 1 μM and about 1.5 M. In another variation, theconcentration of chlorite in the formulations described herein isbetween any of about 1 M and about 1.5 M; between about 1 AM and about100 mM; between about between about 10 AM and about 100 mM; betweenabout 0.1 mM and about 10 mM; between about 0.1 mM and about 500 mM;between about 0.1 mM and about 200 mM; between about 1 mM and about 100mM; between about 0.1 mM and about 5 mM; between about 50 mM and about100 mM; between about 55 mM and about 70 mM; between about 60 mM andabout 65 mM; between about 100 mM and about 500 mM; between about 200 mMand about 400 mM; between about 300 mM and about 700 mM; about 1 mM;about 1.5 mM; about 2 mM; about 2.5 mM; about 3 mM; about 3.5 mM; about4 mM; about 5 mM; about 10 mM; about 20 mM; about 30 mM; about 40 mM;about 50 mM; about 60 mM; about 62 mM; about 65 mM; about 70 mM; about80 mM; about 90 mM; about 100 mM; at least about 0.1 mM; at least about1 mM; at least about 2 mM; at least about 5 mM; at least about 10 mM; atleast about 20 mM; at least about 30 mM; at least about 40 mM; at leastabout 50 mM; at least about 60 mM; at least about 70 mM; at least about80 mM; at least about 90 mM; or at least about 100 mM. In somevariations, the concentration of chlorate in the formulations describedherein is between about 50 mM and about 100 mM. In some variations, theconcentration of chlorate in the formulations described herein isbetween about 55 mM and about 75 mM. In some variations, theconcentration of chlorate in the formulations described herein isbetween about 0.1 mM and about 10 mM. In some variations, theconcentration of chlorate in the formulations described herein isbetween about 1 mM and about 5 mM.

In some variations, the chlorite formulation has a pH no greater thanabout 12.0. In some variations, the pH of the formulation is any of nogreater than about 11.5, about 11.0, about 10.5, about 10.0, about 9.5,about 9.0, about 8.5, about 8.0, about 7.5, about 7.0, about 6.5, orabout 6.0. In some variations, the pH of the formulation is no greaterthan about 11.5. In some variations, the pH of the formulation is nogreater than about 10.5. In some variations, the pH of the formulationis no greater than about 8.5. In some variations, the pH of theformulation is no greater than about 7.5. In some variations, the pH ofthe formulation is between any one or more of about 7 and about 12;between about 7 and about 11.5; between about 7 and about 10.5; betweenabout 7 and about 10; between about 7 and about 9.5; between about 7 andabout 9.0; between about 7 and about 8.5; between about 7 and about 8.0;between about 7 and about 7.5; between about 7.5 and about 8; betweenabout 7.5 and about 8.5; between about 7 and about 8; between about 8and about 9; between about 7.0 and about 8.5; between about 8 and about8.5; between about 8.5 and about 9; between about 7.1 and about 7.7;between about 7.2 and about 7.6; between about 7.3 and about 7.4; about7.0; about 7.1; about 7.2; about 7.3; about 7.4; about 7.5; about 7.6;about 7.7; about 7.8; about 7.9; about 8.0; about 8.1; about 8.2; about8.3; about 8.4; about 8.5; about 8.6; about 8.7; about 8.8; or about8.9. In some variations, the chlorite formulation has a pH of about 7.0to about 9.0. In some variations, the chlorite formulation has a pH ofabout 7.0 to about 8.5. In some variations, the chlorite formulation hasa pH of about 6.0 to about 8.5. In some variations, the chloriteformulation has a pH of about 7.0 to about 8.0. In some variations, thechlorite formulation has a pH of about 7.4.

In some variations, the formulations described herein have a pH asdescribed above, and is formulated for any one or more of parenteral,systemic, or intravenous administration.

In some variations, the formulations described herein have a pH asdescribed above, and have a percentage chlorite purity as describedherein.

In some variations, the formulations described herein have a pH asdescribed above, and have a concentration of chlorite as describedherein. In some embodiments, the aqueous formulations described hereinhave a pH between about 7 and about 11.5, or between about 7.0 and about10, or between about 7.0 and about 9.0, or between about 7.0 and about8.5, or between about 7.1 and about 7.7, and have a concentration ofchlorite between about 1 and about 100 mM. In some embodiments, theaqueous formulations described herein have a pH between about 7 andabout 11.5, or between about 7.0 and about 10, or between about 7.0 andabout 9.0, or between about 7.0 and about 8.5, or between about 7.1 andabout 7.7, and have a concentration of chlorite between about 1 andabout 5 mM. In some embodiments, the aqueous formulations describedherein have a pH between about 7 and about 11.5, or between about 7.0and about 10, or between about 7.0 and about 9.0, or between about 7.0and about 8.5, or between about 7.1 and about 7.7, and have aconcentration of chlorite between about 50 and about 80 mM.

In some embodiments, the aqueous formulations described herein have a pHbetween about 7 and about 11.5, or between about 7.0 and about 10, orbetween about 7.0 and about 9.0, or between about 7.0 and about 8.5, orbetween about 7.1 and about 7.7, wherein the pH was adjusted with a pHadjusting agent that is any one or more of a phosphate, or acetic acid.

In some variations, the formulations described herein are stable withrespect to one or more of pH or chlorite degradation over a period ofany of at least about 1 day, at least about 2 days, at least about 3days, at least about 4 days, at least about 5 days, at least about 6days, at least about 1 week, at least about 2 weeks, at least about 3weeks, at least about 4 weeks, at least about 5 weeks, at least about 6weeks, at least about 7 weeks, at least about 8 weeks, at least about 1month, at least about 2 months, at least about 3 months, at least about4 months, at least about 5 months, or at least about 6 months. In somevariations, the formulations described herein are stable with respect toone or more of pH or chlorite degradation over a period of any of atleast about 1 week. Described herein are stable with respect to one ormore of pH or chlorite degradation over a period of any of at leastabout 1 month. In some variations, the formulations described herein arestable with respect to one or more of pH or chlorite degradation at oneor more of room temperature, refrigerated conditions, or approximately4° C. In some variations, the formulations described herein are stablewith respect to one or more of pH or chlorite degradation underconditions of diminished light or storage in a container that limits theamount of light to which the formulation is subjected. In somevariations, the formulations described herein are stable with respect toone or more of pH or chlorite degradation when stored in the dark.Examples of stable pH, as used herein, means that the pH of theformulation changes by less than any of about 0.1, about 0.2, about 0.3,about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, orabout 1 relative to the pH of the formulation as initially prepared. Insome variations, the pH of the formulation changes by less than about0.2 relative to the pH of the formulation as initially prepared. The pHmay be measured using, for example, a pH meter. Examples of stablechlorite formulations include those in which less than any of about0.1%, less than about 0.2%, less than about 0.3%, less than about 0.4%,less than about 0.5%, less than about 0.6%, less than about 0.7%, lessthan about 0.8%, less than about 0.9%, less than about 1%, less thanabout 2%, less than about 3%, less than about 4%, less than about 5%,less than about 6%, less than about 7%, less than about 8%, less thanabout 9%, or less than about 10% of the chlorite degrades into anon-chlorite ion relative to the amount of chlorite present in theformulation as initially prepared. In some variations, less than about2% of the chlorite degrades into a non-chlorite compound relative to theamount of chlorite present in the formulation as initially prepared. Insome variations, less than about 0.5% of the chlorite degrades into anon-chlorite compound relative to the amount of chlorite present in theformulation as initially prepared. The presence of non-chlorite elementsmay be measured, for example, using gas chromatography (GC), massspectrometry, or other methods known by those of skill in the art.

In some variations, the chlorite formulations described herein compriseno greater than about 5% by weight of deleterious non-chlorite elementsof other commercially available formulations. In some variations, thechlorite formulations described herein comprise any of no greater thanabout 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.3%, about0.25%,about 0.2%, about 0.1%, about 0.05%, or about 0.02%, by weight ofdeleterious non-chlorite elements of other commercially availableformulations. In some variations, the chlorite formulations describedherein comprise any of no greater than about 4% by weight of deleteriousnon-chlorite elements of other commercially available formulations. Insome variations, the chlorite formulations described herein comprise anyof no greater than about 2% by weight of deleterious non-chloriteelements of other commercially available formulations. In somevariations, the chlorite formulations described herein comprise any ofno greater than about 0.5% by weight of deleterious non-chloriteelements of other commercially available formulations. In somevariations, the chlorite formulations described herein comprise any ofno greater than about 0.05% by weight of deleterious non-chloriteelements of other commercially available formulations. In somevariations, the chlorite formulations described herein are substantiallyfree of the deleterious non-chlorite elements of other commerciallyavailable formulations. Nonlimiting examples of methods of detection ofnon-chlorite components include HPLC; SPCS, for example using a NovosepA2 column with 3.6 mM Sodium Carbonate as a mobile phase, 5 g, 250×4.0mm, flow rate 0.8 mL/min; DS-Plus Suppressor, for example using aNovosep A2 column with 3.6 mM Sodium Carbonate as a mobile phase, 5 μ,250×4.0 mm, flow rate 0.8 mL/min; an Allsep A-2 Anion column using 2.1mM NaHCO3/1.6 mM Na2CO3 as a mobile phase, 100×4.6 mm, flow rate 2.0mL/min; an anion HC column using 2.8 mM NaHCO3:2.2 mM Na2CO3 in10%Methanol as a mobile phase, 150×4.6 mm, flow rate 1.4 mL/min; or anAlisep A-2 Anion column using 2.1 mM NaHCO3/1.6 mM Na2CO3 as a mobilephase, 5 μ, 100×4.6 mm, flow rate 1.0 mL/ min See, for example, theAlltech Associates, Inc. Grace Davison line of products and productinformation for details. In some variations, formulations describedherein comprise no greater than about 10%, about 20%, about 30%, about40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 85%,about 90%, or about 95% of the amount of a member of the groupconsisting of, or alternatively any one or more of, chlorate ions andsulfate ions present in an equal weight/volume percent of chloriteformulated as WF10 or a dilution thereof. That is, in some embodiments,when a non-WF10 formulation as described herein comprises a certainpercent w/v of chlorite, such formulation has no greater than about thestated percentage of the amount of one or more of the specifiednon-chlorite components in WF10 or a dilution thereof, wherein the WF10or dilution thereof comprises the same percent w/v of chlorite as isfound in the non-WF 10 formulation with which it is being compared. Insome embodiments, the formulations described herein comprise no greaterthan about 75% of the amount of a member of the group consisting of, oralternatively any one or more of, chlorate ions and sulfate ions presentin an equal weight/volume percent of chlorite formulated as WF10. Insome embodiments, the formulations described herein comprise no greaterthan about 85% of the amount of a member of the group consisting of, oralternatively any one or more of, chlorate ions and sulfate ions presentin an equal weight/volume percent of chlorite formulated as WF10. Insome embodiments, the formulations described herein comprise no greaterthan about 50% of the amount of a member of the group consisting of, oralternatively any one or more of, chlorate ions and sulfate ions presentin an equal weight/volume percent of chlorite formulated as WF 10.

It can be understood from the product insert of WF10 that WF10reportedly includes a ratio of chlorite to chlorate of 100:35.7 (4.25%to 1.5%), a ratio of chlorite to chloride of 100:45.5 (4.25% to 1.9%)and a chlorite to sulfate ratio of 100:16.4 (4.25% to 0.7%).

Examples of deleterious non chlorite components include non-chloritecomponents that cause an adverse reaction when administered tophysiological systems. In some variations, a deleterious non chloritecomponent is associated with one or more indicia of toxicity in one ormore of in vitro or in vivo assays known in the art, or are associatedwith one or indicia of toxicity when administered to a physiologicalsystem, including but not limited to a subject, including but notlimited to a human subject. Deleterious non chlorite components includebut are not limited to sulfate, chlorine dioxide, chlorate, and borate.In some variations, the chlorite formulations described herein aresubstantially free of the deleterious non-chlorite elements of WF10. Insome variations, the chlorite formulations described herein aresubstantially free of sulfate and chlorate ions.

In some variations, the chlorite formulations described herein containless than about 1.9% of chloride ions. In some variations, the chloriteformulation contains any of less than about 1.9%, less than about 1.8%;less than about 1.5%; less than about 1.0%; less than about 0.5%; lessthan about 0.3%; less than about 0.1%; less than about 0.05%; less thanabout 0.01%; less than about 0.001%; between about 0.001 to about 0.1%;between about 0.1 to about 0.5%; between about 0.5 to about 1.0%;between about 1.0 to about 1.5%; or between about 1.5 to about 1.8%byweight of chloride ions. In some variations, the chlorite formulationcontains less than about 0.5% by weight of chloride ions. In somevariations, the chlorite formulation contains less than about 0.24% byweight of chloride ions. In some variations, the chlorite formulationcontains less than about 0.2% by weight of chloride ions. In somevariations, the chlorite formulation contains less than about 0.1% byweight of chloride ions. In some variations, the chlorite formulation issubstantially free of chloride ions. In some variations, the level ofchloride ions is below the level of detection using HPLC.

In some variations, the chlorite formulation contains less than about1.5% of chlorate ions. In further variations, the chlorite formulationcontains any of less than about 1.4%, less than about 1.3%; less thanabout 1.0%; less than about 0.5%; less than about 0.3%; less than about0.1%; less than about 0.01%; less than about 0.001%; between about 0.001to about 0.1%; between about 0.001 to about 0.01%; between about 0.01 toabout 0.1%; between about 0.1 to about 0.5%; between about 0.5 to about1.0%; or between about 1.0 to about 1.4% of chlorate ions. In somevariations, the chlorite formulation is substantially free of chlorateions. In some variations, the chlorite formulation contains less thanabout 0.5% by weight of chlorate ions. In some variations, the chloriteformulation is substantially free of chlorate ions. In some variations,the chlorite formulation contains less than about 0.19% by weight ofchlorate ions. In some variations, the chlorite formulation containsless than about 0.1% by weight of chlorate ions. In some variations, thelevel of chlorate ions is below the level of detection using HPLC.

In some variations, the chlorite formulation contains less than about0.7% of sulfate ions. In further variations, the chlorite formulationcontains any of less than about 0.65%; less than about 0.6%; less thanabout 0.5%; less than about 0.4%; less than about 0.3%; less than about0.2%; less than about 0.1%; less than about 0.08%; less than about0.07%; less than about 0.06%; less than about 0.05%; less than about0.005%; less than about 0.0005%; between about 0.001 to about 0.1%;between about 0.01 to about 0.1%; between about 0.01 to about 0.5%;between about 0.06 to about 0.08%; or between about 0.5 to about 0.65%of sulfate ions. In some variations, the chlorite formulation containsbetween about 0.5 to about 0.65% of sulfate ions. In some variations,the chlorite formulation is substantially free of sulfate ions. In somevariations, the chlorite formulation contains less than about 0.5% byweight of sulfate ions. In some variations, the chlorite formulation issubstantially free of sulfate ions. In some variations, the chloriteformulation contains less than about 0.08% by weight of sulfate ions. Insome variations, the level of sulfate ions is below the level ofdetection using HPLC.

In some variations, the chlorite formulations described herein comprisephosphate ions. In some variations, the chlorite formulations describedherein comprise sodium ions. In some variations, a chlorite formulationcomprises chlorite, an aqueous solvent, sodium, and phosphate ions. Insome variations, the aqueous solvent consists essentially of water. Insome variations, a chlorite formulation consists essentially ofchlorite, water, sodium, and phosphate, and is substantially free ofchlorate. In some variations, a chlorite formulation consistsessentially of chlorite, water, sodium, and phosphate, and issubstantially free of chlorate, and further comprises a pharmaceuticallyacceptable diluent. In a further variation the pharmaceuticallyacceptable diluent is a saline solution.

In some variations, the chlorite formulations described herein compriseno greater than about 10% by weight of by products or impurities presentin commercially available technical grade chlorite. Nonlimiting examplesof by-products or impurities present in commercially available technicalgrade chlorite include chlorate, sulfate, chlorine dioxide, chloride,sodium bicarbonate, and sodium carbonate. In some variations, thechlorite formulations described herein comprise no greater than aboutany of 15%, about 12%, about 10%, about 9%, about 8%, about 7%, about6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about0.3%, about 0.1%, between about 0.1 to about 5%; between about 5 toabout 10%; or between about 10 to about 15% by weight of one or moredegradation products or impurities present in commercially availabletechnical grade chlorite, including but not limited to one or more ofchlorate or sulfate. In some variations, the chlorite formulationsdescribed herein comprise no greater than about 0.5% by weight ofdegradation products or impurities present in commercially availabletechnical grade chlorite, including but not limited to one or more ofchlorate or sulfate. In some variations, the chlorite formulationsdescribed herein comprise no greater than about 5% by weight ofdegradation products or impurities present in commercially availabletechnical grade chlorite, including but not limited to one or more ofchlorate or sulfate. In some variations, the chlorite formulationsdescribed herein are substantially free of the degradation products orimpurities present in commercially available technical grade chlorite,including but not limited to chlorate or sulfate.

In some variations, the formulations described herein are less toxic toa subject than previously reported chlorite formulations at the sameconcentration of chlorite, when administered by at least one of theroutes of administration described herein, including but not limited toby non-topical, systemic, parenteral, or intravenous administration. Insome variations, the toxicity of a chlorite formulation is analyzed fortoxicity using an in vivo or in vitro toxicity assay, includingwell-known toxicity assays. In some variations the chlorite formulationis analyzed for toxicity using the non-specific in vitro toxicity assayin Example 4 below. In some variations, the formulations describedherein exhibit a decreased non-specific toxicity relative to the sameconcentration of chlorite formulated as WF10 using the non-specific invitro toxicity assay in Example 4 below. In some variations, a decreasednon-specific toxicity is a lesser degree of cell death at the sameconcentration of chlorite using the non-specific in vitro toxicity assayin Example 4 below.

In another variation, toxicity is measured according to various responseindicia of toxicity in a subject after administration of the chloriteformulations described herein, as compared to administration of othercommercially available chlorite formulations. In some variations,toxicity is measured relative to systemic administration of chloriteformulated as WF10. In another variation, toxicity is measured relativeto intravenous administration of chlorite formulated as WF 10 to asubject. In some variations, toxicity is measured after administrationto a mammalian subject, including but not limited to a human subject. Insome variations, toxicity is measured as one or more of irritation tothe surface to which the chlorite formulation is exposed, including butnot limited to the gastrointestinal tract, nausea, vomiting, diarrhea,abdominal pain, hemolysis, methemoglobinemia, cyanosis, anuria, coma,convulsions, liver damage, kidney damage, loss of appetite, or weightloss. In some variations, toxicity is measured as one or more ofasthenia, injection site pain, headache, rhinitis, or diarrhea. See, forexample, McGrath MS, Development Of WF10, A Novel Macrophage-RegulatingAgent, Curr Opin Investig Drugs, 3(3):365-73 (Mar. 2002), which isincorporated by reference in its entirety. In another variation,toxicity is measured as anemia. Kempf et al., Comparative Study On TheEffects Of Chlorite Oxygen Reaction Product TCDO (Tetrachlorodecaoxygen)And Sodium Chlorite Solution (NaClO2) With Equimolar Chlorite Content OnBone Marrow And Peripheral Blood Of BDIX Rats, Drugs Under Experimentaland Clinical Research. 19(4):165-1 (1993). In some variations, toxicityis measured as asthenia. In some variations, toxicity is measured asinjection site reaction. In some variations, toxicity is measured asinjection site pain.

Pharmaceutical Formulations

Unless the context clearly indicates otherwise, any of the formulationsdescribed herein may be used in any of the pharmaceutical formulationsdescribed herein.

In some variations, the pharmaceutical formulations described herein aresuitable for administration to a subject. By “suitable foradministration to a subject” is meant that the pharmaceuticalformulation, when obtained from a newly opened bottle and administeredvia the desired route, causes no greater than a clinically acceptablelevel of deleterious side effects.

In some embodiments, the formulations or pharmaceutical formulationsdescribed herein further comprise a saline solution. A saline solution,as used herein, refers to a physiologically acceptable solution with aphysiologically acceptable level of sodium chloride. In someembodiments, the saline solution is isotonic.

Described herein are pharmaceutically acceptable chlorite formulationscomprising one or more pharmaceutically acceptable excipients.Excipients, as used herein, refer to any non-chlorite, non-water, ornon-saline element of a pharmaceutical formulation. Excipients includebut are not limited to carriers, adjuvants, diluents, stabilizers,wetting agents, emulsifiers, buffers, preservatives, flavorings,inactive ingredients, gel formulations, erodible and non-erodiblepolymers, microspheres, liposomes, etc., including combinations of theforegoing, known to skilled artisans and described further herein. Insome variations, the percent by weight of the excipient per the totalvolume of the formulation or pharmaceutical formulation is no greaterthan any of about 10%, about 9%, about 8%, about 7%, about 6%, about 5%,about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, or about 0.05%. In some variations, thepercent by weight of the excipient per the total volume of theformulation or pharmaceutical formulation is no greater than about 1%.In some variations, the percent by weight of the excipient per the totalvolume of the formulation or pharmaceutical formulation is no greaterthan about 3%.

Below is a non-limiting and non-exhaustive list of excipients that arecommonly used in the pharmaceutical arts. These excipients are commonlyused in various types of formulations, including those formulated forintravenous, oral, intramuscular, or parenteral administration. Giventhe reactivity of chlorite, it is likely that some of the excipientslisted below are inappropriate for a given pharmaceutical formulation.Whether or not a particular excipient is inappropriate for a givenpharmaceutical formulation may depend upon the amount of the excipientbeing added to the pharmaceutical formulation. Before adding one or moreof any excipient, including but not limited to the excipients describedherein, to a pharmaceutical formulation of chlorite, it is important toconsider the reactivity of the excipient with chlorite. Some organicmolecules that are commonly used as excipients react with chlorite insuch a way that the excipient is changed, including but not limited to achange that results in increased toxicity of the pharmaceuticalformulation prior to exposure of the excipient to chlorite. In somevariations, the pharmaceutical formulations described herein compriseone or more pharmaceutically acceptable excipients that do not reactwith chlorite. In another variation, the pharmaceutical formulationsdescribed herein comprise one or more pharmaceutically acceptableexcipients that do not diminish the therapeutic effect of thepharmaceutical formulation relative to prior to exposure to theexcipient.

In another variation, the chlorite formulations described hereincomprise one or more pharmaceutically acceptable excipients that do notgenerate one or more of the deleterious non-chlorite elements of othercommercially available chlorite formulations. In some variations, thechlorite formulations described herein comprise an excipient, and aresubstantially free of one or more of the deleterious non-chloriteelements of other commercially available chlorite formulations. In somevariations, the chlorite formulations described herein comprise anexcipient, and are substantially free of one or more of the degradationproducts or impurities of other commercially available chloriteformulations as described herein.

In some variations, the chlorite formulation comprises a stabilizer.Stabilizers include but are not limited to agents that will do any of(1) improve the compatibility of excipients with a container, includinga glass bottle or an encapsulating materials such as gelatin, (2)improve the stability of chlorite (e.g. prevent degradation), or (3)improve formulation stability.

Stabilizers may be selected from, for example, fatty acids, fattyalcohols, alcohols, long chain fatty acid esters, long chain ethers,hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones,polyvinyl ethers, polyvinyl alcohols, hydrocarbons, hydrophobicpolymers, moisture-absorbing polymers, and combinations thereof. Amideanalogues of stabilizers can also be used. The chosen stabilizer maychange the hydrophobicity of the formulation (e.g., oleic acid, waxes),or improve the mixing of various components in the formulation (e.g.,ethanol), control the moisture level in the formula (e.g., PVP orpolyvinyl pyrrolidone), control the mobility of the phase (substanceswith melting points higher than room temperature such as long chainfatty acids, alcohols, esters, ethers, amides etc. or mixtures thereof;waxes), and/or improve the compatibility of the formula withencapsulating materials (e.g., oleic acid or wax). Some of thesestabilizers may be used as solvents/co-solvents (e.g., ethanol).Stabilizers may be present in sufficient amount to inhibit chlorite'sdegradation.

The formulations described herein may contain one or more of a gellingagent or a release modifying agent.

The formulations described herein may contain one or more adjuvantsappropriate for the indicated route of administration. Again, prior tothe addition of any excipient to the formulations described herein, thereactivity of chlorite should be considered with respect to whether theresulting pharmaceutical formulation will be appropriate foradministration via the desired route of administration. Adjuvants withwhich the therapeutic agent may be admixed with include but are notlimited to lactose, sucrose, starch powder, cellulose esters of alkanoicacids, stearic acid, talc, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulphuric acids, acacia, gelatin,sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol. When asolubilized formulation is required the therapeutic agent may be in asolvent including but not limited to polyethylene glycol of variousmolecular weights, propylene glycol of various molecular weights,carboxymethyl cellulose colloidal solutions, methanol, ethanol, DMSO,corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/orvarious buffers. Other adjuvants and modes of administration are wellknown in the pharmaceutical art and may be used in the practice of themethods and formulations described herein. The carrier or diluent mayinclude time delay material, such as glyceryl monostearate or glyceryldistearate alone or with a wax, or other materials well known in theart. The formulations for use as described herein may also include gelformulations, erodible and non-erodible polymers, microspheres, andliposomes.

Additives and diluents normally utilized in the pharmaceutical arts canoptionally be added to the pharmaceutical composition and the liquidformulation. These include thickening, granulating, dispersing,flavoring, sweetening, coloring, and stabilizing agents, including pHstabilizers, other excipients, anti-oxidants (e.g., tocopherol, BHA,BHT, TBHQ, tocopherol acetate, ascorbyl palmitate, ascorbic acid propylgallate, and the like), preservatives (e.g., parabens), and the like.Exemplary preservatives include, but are not limited to, benzylalcohol,ethylalcohol, benzalkonium chloride, phenol, chlorobutanol, and thelike. Some antioxidants provide oxygen or peroxide inhibiting agents andmay be used in the formulations described herein, including but notlimited to, butylated hydroxytoluene, butylhydroxyanisole, propylgallate, ascorbic acid palmitate, α-tocopherol, and the like. Thickeningagents, such as lecithin, hydroxypropylcellulose, aluminum stearate, andthe like, may be used if desired, for example to improve one or morequalities of the formulation, such as the texture.

In some variations, the chlorite formulations described herein aresterile. Sterilization can be by any method that is compatible withchlorite. In some variations, sterilization is via a method that doesnot generate a substantial amount of a degradation product of chlorite.In some variations, sterilization is via a method that does not cause astructural change in chlorite. In some variations, the formulationsdescribed herein are sterile pharmaceutical formulations for parenteralor intravenous administration. In some variations, the chloriteformulations described herein are sterile filtered, for example, througha sterile 0.22 micron filter.

In some variations, the formulations or pharmaceutical formulations aresterile-filterable. In some variations, the chlorite formulationsdescribed herein are formulated for administration by one or more of theroutes of administration described herein. A formulation that is“formulated for administration” by a specified route of administration,as used herein, is a formulation that does not include pharmaceuticalexcipients that are considered inappropriate for the route ofadministration by those of skill in the relevant art. As one example, aformulation that is suitable for intravenous administration would notinclude a toothpaste excipient or carrier intended for topicaladministration, where the excipient or carrier is consideredinappropriate for the specified route of administration by those ofskill in the relevant art.

Methods of purifying chlorite

Described herein are methods of purifying chlorite. It is intended thatthe methods described herein can be used to produce the formulations orpharmaceutical formulations described herein. However, the formulationsand pharmaceutical formulations described herein may also be produced byother methods, and the formulations and pharmaceutical formulationsdescribed herein are not limited to those produced by the methodsdescribed herein.

In some variations, the purification is by subjecting a mixturecomprising chlorite to conditions in which chlorite is in solution butone or more impurities are insoluble. The chlorite is separated from theinsoluble impurities. In some variations, the chlorite is furtherpurified by crystallization of the chlorite from the mixture, andseparation of the chlorite from the remaining mixture. In somevariations, the chlorite is purified from a mixture comprising sodiumchlorite.

Generally, the chlorite ions may be from any source containing chlorite.For example, chlorite may be a chlorite salt, for example alkali metalsalts, sodium chlorite, potassium chlorite, and the like, or a mixtureof chlorite salts. Alternatively, the source of chlorite may be from aformulation comprising chlorite. In some variations, chlorite ispurified from a formulation comprising TCDO or WF10. In anothervariation, chlorite is from a solution comprising sodium chlorite.

In some variations, impure chlorite, including but not limited to impuresodium chlorite, is dissolved in a solvent or a solvent system. In somevariations, any solvent in which chlorite dissolves is used. In anothervariation, any solvent in which chlorite dissolves and with whichchlorite does not react is used. In some variations, the solvent isdistilled water. In some variations, the solvent is a non-organicsolvent.

In some variations impure sodium chlorite is between about 0.1% to about99% per weight of the starting material. As non-limiting examples of thepurity of the chlorite starting material, the chlorite is between aboutany of 0.1% and about 5%; between about 1% and about 5%; between about4% and about 10%; between about 1% and about 15%; between about 15% andabout 25%; between about 5% and about 25%; between about 25% and about50%; between about 50% and about 75%; between about 75% and about 85%;between about 85% to about 95%; between about 60% and about 90%; betweenabout 95% and about 99% per weight of the starting material; at leastabout 50, at least about 60, at least about 70, at least about 80, atleast about 90, or at least about 95% pure. If the impure chlorite is ina solvent, the percent purity is relative to the non-solvent components.In some variations the chlorite is between about 75% and about 85% pure.In some variations the chlorite is between about 85% and about 95% pure.In some variations the chlorite is at least about 85% pure.

In some variations, small amounts of hydrogen peroxide are added to thedissolved chlorite. While not wishing to be bound by theory, theaddition of small amounts of hydrogen peroxide may reduce sodiumchlorate to sodium chlorite. If desired, unreacted hydrogen peroxide maybe subsequently removed. In some variations, hydrogen peroxide is addedafter the initial dissolution of chlorite step and subsequently removedby filtration, for example, by centrifugal filtration.

In some variations, an impure solution of chlorite is subjected toconditions wherein the chlorite remains soluble, but one or more of theimpurities is no longer soluble. One such method is described in RussianPatent No. SU327132, which is hereby incorporated by reference in itsentirety. In some variations, the impure solution is concentrated at anelevated temperature until one or more impurities precipitate. It isenvisioned that the precipitated impurities can include but are notlimited to chlorate, chloride, and sulfate. In some variations theimpure solution is concentrated at a temperature that is any of betweenabout 60 to about 100° C.; between about 65 to about 75° C.; betweenabout 60 to about 80° C.; between about 60 to about 100° C.; betweenabout 70 to about 90° C.; at about 60° C.; at about 65° C.; at about 70°C.; at about 75° C.; or at about 80° C. In some variations, the impuresolution is concentrated at a temperature that is between about 65 toabout 75° C.

In certain variations, the impure solution is concentrated using themethods described herein and under reduced pressure. A skilled artisanis familiar with a range of suitable techniques for providing reducedpressure including but not limited to the application of a vacuum duringconcentration.

The degree to which the chlorite solution is concentrated may be varied.In some variations, the solid to liquid phase volume ratio in thesuspension is no greater than about 1 part to about 12 parts. By way ofone non-limiting example, at least 50% water removal from a startingsolution of chlorite has been demonstrated to result in the eliminationof a significant amount of impurities, for example, chloride and/orchlorate, while maintaining chlorite in solution. One or more impuritiesare thereafter separated from the chlorite. In some variations theimpurities are removed while the mixture is still subject to conditionswherein the chlorite remains soluble, but one or more of the impuritiesare no longer soluble. One method of removing the impurities is byfiltration. If filtration is used, the temperature upon filtration maybe, for example, at an elevated temperature that is similar to thetemperature at which the concentration was performed. In some variationsfiltration is used, and the filtration occurs shortly afterconcentration. The concentrated chlorite solution includes greater than80% pure chlorite by weight. The purity of chlorite in the concentratedsolution can be greater than 85% pure or greater than 90% pure byweight.

The resulting chlorite solution may optionally be again subjected toconditions wherein the chlorite remains soluble, but one or more of theimpurities is no longer soluble. The conditions may be optimized toreduce the same or a different impurity as was reduced in the firstpurification.

In some variations, the chlorite is subjected to conditions wherein thechlorite is not soluble, but the impurities are soluble. In somevariations, chlorite is purified by inducing chlorite to crystallizefrom a solution. In some variations, the chlorite is induced tocrystallize from a concentrated filtrate prepared by the methodsdescribed herein. As one non-limiting example, chlorite may be inducedto crystallize by cooling the chlorite solution. In some variations,chlorite is induced to crystallize by exposure of a chlorite solution toa temperature that is any of no greater than about 10° C., no greaterthan about 0° C., no greater than about −10° C.; no greater than about−20° C.; no greater than about −30° C.; no greater than about −40° C.;between about −15° C. and about −35° C., between about −20° C. and about−30° C.; about 10° C.; about 0° C.; about −10° C.; about −15° C.; about−20° C.; about −25° C.; about −30° C.; about −35° C.; or about −40° C.In some variations, the chlorite is induced to crystallize by exposureof a chlorite solution to a temperature no greater than about −20° C. Insome variations, the chlorite is

In general, the chlorite may be cooled at different rates, such as astepwise placement into increasingly cool environments, or the chloriteformulation may be placed in a single cooling environment. The chloriteformulation may be cooled over a period of, for example, 12 to 24 hours.Longer or shorter periods may also be utilized. In some variations, thechlorite formulation is cooled over a period of between about 12 andabout 14, about 14 and about 16, about 16 and about 18, about 18 andabout 20, about 20 and about 22, or about 22 to about 24 hours.

In some variations, chlorite is harvested from a mixture comprisingchlorite solids. The solids may be harvested by various methods known bythose of skill in the art, including but not limited to by filtration.In some variations, chlorite solids are harvested from a mixturecomprising chlorite that has been cooled to crystallize the chloritesolids.

In some variations, a mixture comprising chlorite solids is filtered asa frozen mixture comprising chlorite melts. When filtration isspecified, those of skill in the art can determine an appropriate methodof filtration. In some variations, suction filtration is used toseparate chlorite solids from a mixture. The chlorite solids can be inthe form of a slush. In another variation, centrifugal filtration isused to separate chlorite solids from a mixture. During centrifugalcentrifugation, water remaining in the mixture containing chloritesolids melts and can be eliminated while the chlorite solids remainassociated with a filter. In some variations, centrifugal filtration isperformed using a 50 micron filter at 1200 rpm. In some variations thefilter is about 50 to about 250 microns. In some variations, the rpm areabout 1000 to about 3600. In another variation, the force of gravity isused to separate the solids from the rest of the mixture. The resultingchlorite solids can be in a hydrated form.

The chlorite may optionally be recrystallized by the above or adifferent method. In some variations the chlorite is recrystallized togive chlorite of increased purity relative to the firstrecrystallization.

Described herein are mixtures comprising chlorite, wherein the chloriteis any of greater than about 70%, greater than about 80%, greater thanabout 85%, greater than about 90%, greater than about 95%, greater thanabout 99%; between about 70-80%; between about 80-90%; between about90-99%; about 70%; about 75%; about 80%; about 85%; about 90%; about95%; or about 99% pure. If a solvent is present, including but notlimited to water, the percentage purity is relative to the non-solventcomponents. Described herein are mixtures comprising chlorite, whereinthe chlorite is between about 70-80% pure. Described herein are mixturescomprising chlorite, wherein the chlorite is between about 80-90% pure.

Purified chlorite may be dissolved in an aqueous solvent to give achlorite solution of the desired concentration or molarity. As oneexample, the purified chlorite may be dissolved in distilled water or asaline solution, or any solvent, mixture of solvents, or solvent systemthat is capable of dissolving chlorite, or a solvent that ispharmaceutically acceptable for administration in a subject. Such asolvent is readily identified by those of skill in the art. See forexample, Remington: The Science and Practice of Pharmacy, TwentiethEdition, Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000),which is incorporated herein by reference in its entirety. In somevariations, the solvent is water. The resulting chlorite solution caninclude greater than 90% pure chlorite ions by weight. In somevariations, the purity of chlorite in the solution can be greater than95% pure chlorite ions or greater than 99% pure chlorite ions by weight.In one variation, wherein the purified chlorite is dissolved in water toan approximately 1 M concentration, the solution can include a pH, forexample, of about pH 8.5 to about pH 10.

Alternatively, the chlorite may be suspended in a suspending medium,including but not limited to any suspending medium that is capable ofsuspending chlorite, or a suspending medium that is pharmaceuticallyacceptable for administration in a subject. Such a suspending medium isreadily identified by those of skill in the art. See, for example,Remington, cited above.

Briefly, one method of preparing a formulation comprising chlorite asdisclosed herein can be achieve through the steps of: (a) concentratinga chlorite solution at a temperature between 60° C. to about 100° C.,whereby impurities precipitate from the solution, (b) removing theimpurities from the concentrated solution by filtration, (c) inducingcrystallization of chlorite from the concentrated solution, (d)harvesting the resulting chlorite solids by filtration, and (e)dissolving the chlorite solids in an aqueous solvent. It is envisionedthat in some variations the resulting aqueous formulation of chloritecomprises a purity of at least 80% chlorite, at least 85% chlorite, atleast 90% chlorite, at least 95% chlorite or at least 99% chlorite.

The chlorite may also be emulsified in an emulsification system,including but not limited to any emulsification system that is capableof emulsifying chlorite, or an emulsification system that ispharmaceutically acceptable. Such an emulsification system is readilyidentified by those of skill in the art. See, for example, Remington,cited above.

Good Manufacturing Practice (GMP) Formulations and Methods

In general in another aspect, the invention provides chloriteformulations prepared under a standard relating to manufacture andquality control of pharmaceutical goods, called GMP (Good ManufacturingPractice), which has been enacted in many countries. GMP specifies,because of the importance of pharmaceutical goods which can decide one'slife, that it is required to make quality control such as chemicalanalysis, to maintain optimum equipments and environments formanufacturing pharmaceutical goods, and to take care of allmanufacturing practices including manufacture, packaging, display, andstorage of pharmaceutical products and materials. GMP further refers tothe Good Manufacturing Practice Regulations promulgated by the US Foodand Drug Administration under the authority of the Federal Food, Drug,and Cosmetic Act. GMP is also sometimes referred to as “cGMP”. The “c”stands for “current,” reminding manufacturers that they must employtechnologies and systems which are up-to-date in order to comply withthe regulation. Systems and equipment used to prevent contamination,mix-ups, and errors, which may have been “top-of-the-line” 20 years ago,may be less than adequate by today's standards.

Accordingly, GMP is well known to those of skill in the art in relationto the manufacture of pharmaceutical goods. It is envisioned that thecompositions and methods described herein can be manufactured andperformed under GMP or cGMP.

Methods of Adjusting the pH of Formulations Sensitive to pH

Described herein are methods of adjusting the pH of formulations andpharmaceutical formulations comprising chlorite. It is intended that themethods described herein can be used to produce the formulations orpharmaceutical formulations described herein. However, the formulationsand pharmaceutical formulations described herein may also be produced byother methods, and the formulations and pharmaceutical formulationsdescribed herein are not limited to those produced by the methodsdescribed herein.

Some compounds or formulations are sensitive to high local acidity oralkalinity. Yet it may be desired to adjust the pH of such compounds orformulations. Described herein are methods of adjusting the pH offormulations sensitive to high local acidity or alkalinity. Preferred pHadjusting agent(s) or pH adjusting compound(s) are weak acids or weakbases having a pKa of about 4 to about 9, a pKa of about 5 to about 9,or a pKa of about 5 to about 8, or a pKa of about 6 to about 7.5.Examples include, but are not limited to a phosphate buffer having a pKaof about 4 to about 9 as well known in the field, for example, monobasicphosphates, or monosodium phosphate, and lower alkanoic acids, forexample, acetic acid or propionic acid. In some variations, the pH of aformulation sensitive to acidity is lowered to between about 7 and about11.5 using a pH adjusting compound that does not expose the formulationto acidity, including but not limited to a high local acidity in thearea around the pH adjusting compound. In some variations, the pH of aformulation sensitive to acidity is lowered to between about 7 and about10 using a pH adjusting compound that does not expose the formulation toacidity, including but not limited to a high local acidity in the areaaround the pH adjusting compound. In some variations, the pH of aformulation sensitive to acidity is lowered to between about 7 and about9.5 using a pH adjusting compound that does not expose the formulationto acidity, including but not limited to a high local acidity in thearea around the pH adjusting compound. In some variations, the pH of aformulation sensitive to acidity is lowered to between about 7 and about9.0 using a pH adjusting compound that does not expose the formulationto acidity, including but not limited to a high local acidity in thearea around the pH adjusting compound. In some variations, the pH of aformulation sensitive to acidity is lowered to between about 7 and about8.5 using a pH adjusting compound that does not expose the formulationto acidity, including but not limited to a high local acidity in thearea around the pH adjusting compound. In some variations, the pH of aformulation sensitive to acidity is lowered to between about 7.1 andabout 7.7 using a pH adjusting compound that does not expose theformulation to acidity, including but not limited to a high localacidity in the area around the pH adjusting compound.

“High local acidity,” as used herein, refers to the pKa of one or moremolecules local to a chlorite molecule, as opposed to the overallacidity of a solution as would be measured, for example, using a pHmeter. To determine whether a pH-adjusting agent will subject chloriteto high local acidity, the pKa of the pH adjusting agent can beidentified using, for example, the CRC Handbook of Chemistry and Physics(86th Edition, David R. Lide ed., CRC Press, 2005).

Lowering the pH of chlorite formulations has been challenging becausemany pH adjusting agents expose compounds or formulations to highacidity in the local area of the molecules of the pH-adjusting compound.In the presence of high local acidity, some amount of non-chloritecompounds are generated, for example, chlorate and/or chlorine dioxide.See, for example, Ullmann's Encyclopedia of Industrial Chemistry, Vol.A6, Ed. Wolfgang Gerhartz, 5th Ed. (1986), which is incorporated hereinby reference in its entirety. Such degradation products may not bedesired in formulations for parenteral or systemic administration tophysiological systems, for example, because they are not inactive inphysiological systems. Some such degradation products result intoxicity, including but not limited to the toxicities, including but notlimited to non-specific toxicity, described herein.

Unless the context makes clear, the pH of any of the formulations orpharmaceutical formulations described herein may be adjusted using themethods described herein.

In some variations, the activity of a therapeutic agent, including butnot limited to chlorite, is diminished by exposure to high localacidity. “Diminished activity,” as used herein, refers to an activity ofa therapeutic agent that is qualitatively or quantitatively inferior tothat of the therapeutic agent prior to the exposure to high localacidity. As one example, a changed activity that is qualitatively orquantitatively inferior to that of the therapeutic agent prior to theexposure to high local acidity would be a lesser efficacy of woundhealing, or a lesser efficacy in treating one or more of the diseases orconditions described herein. In some variations, the changed activity isany of at least about 3%, at least about 5%, at least about 10%, atleast about 15%, at least about 20%, or at least about 25% lower thanthe activity of the therapeutic agent prior to the exposure to highlocal acidity. In some variations, the changed activity is at leastabout 5% lower than the activity of the therapeutic agent prior to theexposure to high local acidity.

In some variations, the pH of a chlorite formulation is adjusted to anyone or more of the pH levels described in the formulations section orelsewhere herein. In some variations the pH of a chlorite formulationdescribed between about 7 and about 11.5. In some variations, the methodcomprises lowering the pH of a formulation comprising chlorite to any ofbetween about between about 7 and about 11; between about 7 and about10.5; between about 7 and about 10; between about 7 and about 9.5;between about 7 and about 9; between about 7 and about 8.5; betweenabout 7 and about 8.0; between about 7 and about 7.5; between about 7.5and about 8; between about 7.5 and about 8.5; between about 7 and about8; between about 7.1 and about 7.7; between about 7.2 and about 7.6;between about 7.3 and about 7.5; between about 8 and about 9; betweenabout 8 and about 8.5; between about 8.5 and about 9; about 7.0; about7.1; about 7.2; about 7.3; about 7.4; about 7.5; about 7.6; about 7.7;about 7.8; about 7.9; about 8.0; about 8.1; about 8.2; about 8.3; about8.4; about 8.5; about 8.6; about 8.7; about 8.8; or about 8.9 using a pHadjusting agent that does not expose the chlorite to a high localacidity. In some variations, the method comprises lowering the pH of aformulation comprising chlorite to between about 7 and about 8.5. Insome variations, the method comprises lowering the pH of a formulationcomprising chlorite to between about 7 and about 8.0. In somevariations, the method comprises lowering the pH of a formulationcomprising chlorite to between about 7.1 and about 7.7. In somevariations, the method comprises lowering the pH of a formulationcomprising chlorite to about 7.4.

In one nonlimiting example, the pH of a mixture comprising chlorite isadjusted using a pH adjusting agent that does not subject the chloriteto a local pH of below 7 when exposed to the mixture comprisingchlorite. In some variations, the pH adjusting agent is monosodiumphosphate. In further variations, monosodium phosphate is used as asolid or in solution. In some variations, the pH adjusting agent isacetic acid.

In some variations, the pH of chlorite is adjusted by adding chlorite oran aqueous mixture comprising chlorite to a solution containing buffer.In some variations, the pH of chlorite is adjusted by adding chlorite oran aqueous mixture comprising chlorite to a solution of a phosphatebuffer.

In some variations, one or more pH-adjusting agents are used to adjustthe pH of a chlorite solution or mixture, and the resulting solution ormixture is analyzed for the presence of degradation products ofchlorite, including but not limited to degradation products generated byhigh local acidity. In some variations, pH-adjusting agents such asacetic acid, or monosodium phosphate are used to adjust the pH of achlorite solution or mixture, and the resulting solution or mixture isanalyzed for the presence of chlorate or chlorine dioxide.

In some variations, the resulting solution or mixture is analyzed fordegradation products using well known analytical methods such as HPLC,mass spectrometry, etc. In another variation, the resulting solution ormixture is analyzed for degradation products using a toxicity assay,including well-known toxicity assays. In some variations the resultingsolution or mixture is analyzed for impurities using a non-specifictoxicity assay such as the one described in Example 4 below.

In some variations, the pH of a chlorite formulation is adjusted after achlorite purification step.

In some variations, the pH of a chlorite formulation is adjusted tobetween about 7 and about 11.5 without the generation of chloritedegradation products that are a result of high local acidity. In somevariations, the pH of a chlorite formulation is adjusted to betweenabout 7 and about 8.0 without the generation of chlorite degradationproducts that are a result of high local acidity. In some variations,the pH of the chlorite formulation is adjusted to any of between about 7and about 11; between about 7 and about 10.5; between about 7 and about10; between about 7 and about 9.5; between about 7 and about 9; betweenabout 7 and about 8.5; between about 7 and about 8; between about 7 andabout 7.5; between about 7.5 and about 8; between about 7.5 and about8.5; between about 7 and about 8; between about 8 and about 9; betweenabout 8 and about 8.5; or between about 8.5 and about 9 without thegeneration of chlorite degradation products that are a result of highlocal acidity.

Methods of Treatment

As noted previously, numerous conditions can be treated using thechlorite formulations described herein. Unless the context indicatesotherwise, all of the formulations and pharmaceutical formulationsdescribed herein may be used in the methods of treatment describedherein. As used herein and as well understood in the art, examples oftreatment include obtaining beneficial or desired results, includingclinical results. As described herein, nonlimiting examples ofbeneficial or desired clinical results include one or more of, but arenot limited to, alleviation or amelioration of one or more symptoms,diminishment of extent of a condition, including a disease, stabilized(i.e., not worsening) state of a condition, including diseases,preventing spread of disease, delay or slowing of condition, includingdisease, progression, amelioration or palliation of the condition,including disease, state, and remission (whether partial or total),whether detectable or undetectable. In some variations, the chloriteformulations described herein are used to achieve one or more oftreating, preventing, delaying the onset of, or causing the regressionof the diseases or conditions described herein.

In general, a therapeutically effective amount of a formulation isadministered to a subject. An “effective amount,” which is also referredto herein as a “therapeutically effective amount,” of a therapeuticagent for administration as described herein is that amount of thetherapeutic agent that provides the therapeutic effect sought whenadministered to the subject. A therapeutically effective amount may beachieved in a single administration or after multiple administrations.The achieving of different therapeutic effects may require differenteffective amounts of therapeutic agent. For example, the therapeuticallyeffective amount of a therapeutic agent used for preventing a disease orcondition may be different from the therapeutically effective amountused for treating, inhibiting, delaying the onset of, or causing theregression of the disease or condition. In addition, the therapeuticallyeffective amount may depend on the age, weight, the bioavailability ofthe compound, the severity of the disease or condition, and other healthconditions of the subject as is well know to those versed in the diseaseor condition being addressed. Thus, the therapeutically effective amountmay not be the same in every subject to which the therapeutic agent isadministered.

To determine whether a level of therapeutic agent is a “therapeuticallyeffective amount” to treat the diseases or conditions described herein,the chlorite formulations may be administered in appropriate animalmodels for the diseases or conditions of interest, and the effects maybe observed to determine whether the treatment was effective in theanimal model. The appropriate level for a different subject, includingbut not limited to a human subject, may be estimated therefrom usingmethods known by those of skill in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an 1050 of the particular compound as measured in anin vitro assay. Calculating dosages to achieve such circulating blood orserum concentrations, taking into account the bioavailability of theparticular active agent, is well within the capabilities of skilledartisans. For guidance, the reader is referred to Fingl & Woodbury,“General Principles,” In: Goodman and Gilman's The Pharmaceutical Basisof Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press,which is hereby incorporated by reference in its entirety, and thereferences cited therein.

The chlorite formulations described herein can be administered alone, oradministered in combination with or adjunctive to other common therapiesfor treating the diseases or conditions described herein. Administrationof the chlorite formulation may be prior to, subsequent to, orconcurrent with one or more other treatments, including but not limitedto treatments using other active agents or non-pharmaceutical therapiessuch as radiotherapy. In some variations the chlorite or othertherapeutic agents are used in accordance with their standard or commondosages, as specified in the prescribing information accompanying othercommercially available chlorite formulations (see also, the prescribinginformation in the 2005 Edition of The Physician's Desk Reference), thedisclosures of which are incorporated herein by reference).

As mentioned above, chlorite has been used to treat various diseases orconditions using previously described chlorite formulations. Unless thecontext makes otherwise clear, all of the chlorite formulations andpharmaceutical formulations described herein may be used to treatdiseases or conditions treated with previously described chloriteformulations. For example, chlorite has been used to treat infectionsand to cause regeneration of bone marrow. See, for example, U.S. Pat.No. 4,725,437 and U.S. Pat. No. 4,851,222, each of which is incorporatedherein by reference in its entirety. Chlorite has also been used totreat HIV, recurrent prostate cancer, cystitis, and chronic activehepatitis C disease. See, for example, McGrath et al., Development ofWF10, a novel macrophage-regulating agent, Curr Opin Investig Drugs,3(3):365-73 (March 2002); U.S. Pat. No. 6,086,922, each of which isincorporated herein by reference in its entirety.

Other non-limiting examples of diseases or conditions that may betreated with the formulations and pharmaceutical formulations describedherein include those described in US Patent Pub. No. 2005/0181068 (Ser.No. 11/042,816) to McGrath (“McGrath”), which is incorporated herein byreference in its entirety. McGrath describes methods of treatingneurodegenerative diseases by administering chlorite in an effectiveamount to treat such diseases. In some variations, the neurodegenerativedisease or disorder is a macrophage-associated neurodegenerative diseaseor disorder. In some variations, the neurodegenerative disease ordisorder treated using the formulations and pharmaceutical formulationsdescribed herein is amyotrophic lateral sclerosis (ALS), Alzheimer'sdisease (AD), multiple sclerosis (MS), pathogen-associated neuraldiseases or symptoms, such as viral infection, including but not limitedto HIV-associated dementia (HAD), or HCV infection. In some variations,ALS is treated using the formulations and pharmaceutical formulationsdescribed herein. In some variations, AD is treated using theformulations and pharmaceutical formulations described herein.

It is envisioned that neoplasia may be treated with the formulations andpharmaceutical formulations described herein. Neoplasia is generallydefined as abnormal, disorganized growth in a tissue or organ. Such agrowth can be in the form of a mass, often called a neoplasm, tumor orcancer. Neoplasms can be benign or malignant lesions. Malignant lesionsare often called cancer. The National Institute of Health lists thirteencancers as the most frequently diagnosed in the United States, eachhaving an estimated annual incidence for 2006 at 30,000 cases or more.These most frequently diagnosed cancers include: bladder cancer,melanoma, breast cancer, non-Hodgkin's lymphoma, colon and rectalcancer, pancreatic cancer, endometrial cancer, prostate cancer, kidney(renal cell) cancer, skin cancer (non-melanoma), leukemia, thyroidcancer and lung cancer. Source:http://www.cancer.gov/cancertopics/commoncancers. Last accessed Sep. 12,2006.

An extensive listing of cancer types includes but is not limited toacute lymphoblastic leukemia (adult), acute lymphoblastic leukemia(childhood), acute myeloid leukemia (adult), acute myeloid leukemia(childhood), adrenocortical carcinoma, adrenocortical carcinoma(childhood), AIDS-related cancers, AIDS-related lymphoma, anal cancer,astrocytoma (childhood cerebellar), astrocytoma (childhood cerebral),basal cell carcinoma, bile duct cancer (extrahepatic), bladder cancer,bladder cancer (childhood), bone cancer (osteosarcoma/malignant fibroushistiocytoma), brain stem glioma (childhood), brain tumor (adult), braintumor—brain stem glioma (childhood), brain tumor—cerebellar astrocytoma(childhood), brain tumor—cerebral astrocytoma/malignant glioma(childhood), brain tumor—ependymoma (childhood), braintumor—medulloblastoma (childhood), brain tumor—supratentorial primitiveneuroectodermal tumors (childhood), brain tumor—visual pathway andhypothalamic glioma (childhood), breast cancer (female, male,childhood), bronchial adenomas/carcinoids (childhood), Burkitt'slymphoma, carcinoid tumor (childhood), carcinoid tumor(gastrointestinal), carcinoma of unknown primary site (adult andchildhood), central nervous system lymphoma (primary), cerebellarastrocytoma (childhood), cerebral astrocytoma/malignant glioma(childhood), cervical cancer, chronic lymphocytic leukemia, chronicmyelogenous leukemia, chronic myeloproliferative disorders, coloncancer, colorectal cancer (childhood), cutaneous t-cell lymphoma,endometrial cancer, ependymoma (childhood), esophageal cancer,esophageal cancer (childhood), Ewing's family of tumors, extracranialgerm cell tumor (childhood), extragonadal germ cell tumor, extrahepaticbile duct cancer, eye cancer (intraocular melanoma and retinoblastoma),gallbladder cancer, gastric (stomach) cancer, gastric (stomach) cancer(childhood), gastrointestinal carcinoid tumor, gastrointestinal stromaltumor (gist), germ cell tumor (extracranial (childhood), extragonadal,ovarian), gestational trophoblastic tumor, glioma (adult), glioma(childhood: brain stem, cerebral astrocytoma, visual pathway andhypothalamic), hairy cell leukemia, head and neck cancer, hepatocellular(liver) cancer (adult primary and childhood primary), Hodgkin's lymphoma(adult and childhood), Hodgkin's lymphoma during pregnancy,hypopharyngeal cancer, hypothalamic and visual pathway glioma(childhood), intraocular melanoma, islet cell carcinoma (endocrinepancreas), Kaposi's sarcoma, kidney (renal cell) cancer, kidney cancer(childhood), laryngeal cancer, laryngeal cancer (childhood),leukemia—acute lymphoblastic (adult and childhood), leukemia, acutemyeloid (adult and childhood), leukemia—chronic lymphocytic,leukemia—chronic myelogenous, leukemia—hairy cell, lip and oral cavitycancer, liver cancer (adult primary and childhood primary), lungcancer—non-small cell, lung cancer—small cell, lymphoma—AIDS-related,lymphoma—Burkitt's, lymphoma—cutaneous t-cell, lymphoma—Hodgkin's(adult, childhood and during pregnancy), lymphoma—non-Hodgkin's (adult,childhood and during pregnancy), lymphoma—primary central nervoussystem, macroglobulinemia—Waldenstrom's, malignant fibrous histiocytomaof bone/osteosarcoma, medulloblastoma (childhood), melanoma,melanoma—intraocular (eye), Merkel cell carcinoma, mesothelioma (adult)malignant, mesothelioma (childhood), metastatic squamous neck cancerwith occult primary, multiple endocrine neoplasia syndrome (childhood),multiple myeloma/plasma cell neoplasm, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,myelogenous leukemia, chronic, myeloid leukemia (adult and childhood)acute, myeloma—multiple, myeloproliferative disorders—chronic, nasalcavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngealcancer (childhood), neuroblastoma, non-small cell lung cancer, oralcancer (childhood), oral cavity and lip cancer, oropharyngeal cancer,osteosarcoma/malignant fibrous histiocytoma of bone, ovarian cancer(childhood), ovarian epithelial cancer, ovarian germ cell tumor, ovarianlow malignant potential tumor, pancreatic cancer, pancreatic cancer(childhood), pancreatic cancer—islet cell, paranasal sinus and nasalcavity cancer, parathyroid cancer, penile cancer, pheochromocytoma,pineoblastoma and supratentorial primitive neuroectodermal tumors(childhood), pituitary tumor, plasma cell neoplasm/multiple myeloma,pleuropulmonary blastoma, pregnancy and breast cancer, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, renal cell (kidney) cancer (childhood), renal pelvisand ureter—transitional cell cancer, retinoblastoma, rhabdomyosarcoma(childhood), salivary gland cancer, salivary gland cancer (childhood),sarcoma—Ewing's family of tumors, sarcoma—Kaposi's, sarcoma—soft tissue(adult and childhood), sarcoma—uterine, Sézary syndrome, skin cancer(non-melanoma), skin cancer (childhood), skin cancer (melanoma), skincarcinoma—Merkel cell, small cell lung cancer, small intestine cancer,soft tissue sarcoma (adult and childhood), squamous cell carcinoma,squamous neck cancer with occult primary—metastatic, stomach (gastric)cancer, stomach (gastric) cancer (childhood), supratentorial primitiveneuroectodermal tumors (childhood), testicular cancer, thymoma(childhood), thymoma and thymic carcinoma, thyroid cancer, thyroidcancer (childhood), transitional cell cancer of the renal pelvis andureter, trophoblastic tumor, gestational, ureter and renalpelvis—transitional cell cancer, urethral cancer, uterinecancer—endometrial, uterine sarcoma, vaginal cancer, visual pathway andhypothalamic glioma (childhood), vulvar cancer, Waldenström'smacroglobulinemia, and Wilms' tumor. Source:http://www.cancer.gov/cancertopics/alphalist. Last accessed Sep. 12,2006.

Routes of Administration

Unless the context indicates otherwise, all of the formulations andpharmaceutical formulations described herein may be administered by anyof systemic, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, intracisternal injection or infusion, subcutaneousinjection, or implant), by inhalation spray, nebulised or aerosolizedusing aerosol propellants, nasal, vaginal, rectal, sublingual, urethral(e.g., urethral suppository), by infusion, intraarterial, intrathecal,intrabronchial, subcutaneous, intradermal, intravenous, intracervical,intraabdominal, intracranial, intrapulmonary, intrathoracic,intratracheal, nasal routes, oral administration that delivers thetherapeutic agent systemically, drug delivery device, or by a dermalpatch that delivers the therapeutic agent systemically, transdermally ortransbuccally. In some variations, the formulation is formulated forother than oral or transbuccal administration.

In some variations, the formulations described herein are notadministered topically.

In some embodiments, the formulations, pharmaceutical formulations, andmethods of administration and treatment described herein are suitablefor use in any warm- or cold-blooded animal. In some embodiments, theformulations, pharmaceutical formulations, and methods of administrationand treatment described herein are suitable for use in a ma mmal,including in the veterinary context, including domestic pets (such ascats, dogs, rabbits, birds, horses, etc.) and agricultural animals (suchas bovine, ovine, fowl, etc.). In some variations, the formulations,pharmaceutical formulations, and methods of administration and treatmentdescribed herein are suitable for use in primates, including but notlimited to humans.

Kits and Articles of Manufacture

Unless the context makes otherwise clear, all of the formulations andpharmaceutical formulations described herein may be used in the kitsdescribed herein. Provided herein are kits for administration ofchlorite or pharmaceutical formulations comprising chlorite that mayinclude a unit dosage amount of a chlorite formulation as describedherein. In some variations, the kits comprise suitable packaging. Insome variations, the kits comprise instructions for use of the chloriteformulations to treat various diseases or conditions. Accordingly, thekits may be used for any of the treatment methods described herein, andin some embodiments contain suitable instructions for practicing any ofthe treatment methods described herein. In some embodiments, the kitsare used to treat any one or more of the diseases or conditionsdescribed herein. Kits may also comprise an aid to administration of thechlorite formulation, such as an inhaler, spray dispenser (e.g. nasalspray), syringe for injection or pressure pack for capsules, tablets, orsuppositories.

The chlorite formulations described herein may be assembled in the formof kits. In some variations the kit provides the chlorite and reagentsto prepare an aqueous chlorite formulation for administration. In somevariations the formulation is an aqueous solution. In some variationsthe formulation is a sterile solution. In some variations, a kitprovides a pharmaceutically acceptable diluent, either already mixedwith the formulations or formulations described herein or provided in aseparate container from the formulations or pharmaceutical formulationsdescribed herein. In some variations, the diluent is a saline solution.In some variations, the composition comprises a dry (such aslyophilized) composition that can be reconstituted or dissolved to formthe formulations or pharmaceutical formulations described herein. Whenthe formulation is in a dry form, the kit may comprise one or more of apharmaceutically acceptable solvent, diluent, and a pH adjusting agent,either separately from or as part of the diluent. In some variations, akit or article of manufacture comprises chlorite in dry form, apharmaceutically acceptable solvent, and pH adjusting agent. In somevariations the pH adjusting agent is incorporated into the solvent. Insome variations, a kit or article of manufacture comprises, chlorite indry form, a pharmaceutically acceptable solvent, a pharmaceuticallyacceptable diluent, and pH adjusting agent. In some variations the pHadjusting agent is incorporated into the diluent. In some variations,the formulations or pharmaceutical formulations described herein aresterile, reconstituted formulations. In some variations, theformulations or pharmaceutical formulations described herein aresterile, reconstituted formulations in unit dosage form. In somevariations, the formulations or pharmaceutical formulations describedherein are sterile, reconstituted formulations in unit dosage form insuitable packaging.

The kit may contain a device for administration or for dispensing thecompositions, including, but not limited to one or more syringes,pipettes, transdermal patches, or inhalants.

The kit may include other therapeutic compounds or formulations for usein conjunction with the formulations described herein. These compoundsmay be provided in a separate form, or mixed with the chloriteformulations or pharmaceutical formulations described herein.

In some variations the kit includes instructions for preparation andadministration of the formulation. In some variations the kit includesinstructions as to side effects of the formulation. In another variationthe kit optionally includes any other relevant information. Theinstructions may be in any suitable format, including, but not limitedto, printed matter, videotape, computer readable disk, or optical disc.The instructions may be located inside the housing or outside thehousing, and may be printed on the interior or exterior of any surfaceforming the housing that renders the instructions legible.

Described herein are kits for treating an individual who suffers from oris susceptible to a disease or condition treatable by the chloriteformulations described herein, comprising a container comprising a unitdosage amount of a chlorite formulation as described herein, andinstructions for use. The container may be any of those known in the artand appropriate for storage and delivery of oral, intravenous, systemic,parenteral, rectal, urethral, transdermal, or inhalation formulations.

Kits may also be provided that contain sufficient dosages of thechlorite or chlorite formulation to provide effective treatment for anindividual for an extended period, including but not limited to any ofabout a week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeksor about 8 weeks or more.

As described herein and shown in FIG. 2, in certain embodiments a kit201 can include a housing or container 203 for housing variouscomponents. As shown in FIG. 2 and described herein, the kit 201 canoptionally include instructions 207 as well as reagents 205, for examplethe formulations described herein. Other embodiments of the kit 201 areenvisioned wherein the components include various additional featuresdescribed herein.

Also provided herein are articles of manufacture comprising theformulations or pharmaceutical formulations described herein, or unitdosage forms in suitable packaging, including but not limited to vialsor vessels, including but not limited to sealed vials or vessels andsterile sealed vials or vessels. Non-limiting examples of suitablepackaging for the formulations and pharmaceutical formulations describedherein are known in the art, and include, for example, any of vials(such as sealed vials), vessels (such as sealed vessels), ampules,bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags),and the like. Such packaging may optionally limit the amount of light towhich the formulation is exposed. These articles of manufacture mayfurther be sterilized and/or sealed.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLES Example 1 Purification of Chlorite

This procedure was performed in diminished light, e.g., with overheadlights off, and out of direct sunlight.

Sodium Chlorite (80 wt %, Sigma-Aldrich lot #09911CD) was dissolved in1000 mL of distilled water. The flask was mounted to a rotaryevaporator, and the bath temperature set to 70° C. Vacuum was applied,and increased until the water began to distill over in a controlledmanner. The vacuum was applied until the mixture put down a load ofsolids, and 550 mL of water had distilled over. Using a coarse sinteredglass funnel, the solids were removed by suction filtration of the hotsolution. These solids were mostly sodium chloride.

The filtrate was stored at −25° C. for a period of time sufficient toprecipitate the chlorite (approximately 24 hours). The entire mixturefroze solid. The frozen mixture was broken up and centrifugally filteredwhile cold. Purified sodium chlorite was collected as the frozen solidmelted. The centrifuge had a 12-inch stainless steel basket, 50 micronpolypropylene bag, and was run at 2000 rpm. HPLC analysis using anion-separating column and ion detector showed 99.04% purity. Thematerial is presumed to be a mixture of hydrate and non-hydrate.

Example 2 Purification of Chlorite

The method described in Example 1 was performed, but using coarsesintered glass suction filtration rather than centrifugal filtration forthe cold filtration. After the first filtration, chlorite purity afterthe first crystallization was 91.9%. The crystallization step wasrepeated a second time. After the second recrystallization/suctionfiltration, the chlorite was 99.5% pure.

Example 3 Adjustment of Chlorite Formulation pH

To prepare a chlorite formulation at a lower pH, sodium chloritepurified by the method of Example 2 was dissolved in distilled water andstirred using a magnetic stirrer. A calibrated pH probe was put in thesolution. Small amounts of monosodium phosphate monohydrate were added,until the pH reached and stabilized at 7.62. In the event of the pHdrifting lower than the target pH, the pH can be adjusted back with 0.1N NaOH.

This solution was sampled, and assayed for sodium chlorite content byHPLC. Column: Novosep A-2 Alltech 250×4 mm; eluant: 3.6 mM sodiumcarbonate. Rate: 0.8 mL/min. Detected with a suppressed Alltech 650conductivity detector. Quantitation was performed by standard iodimetry.See Inorganic Syntheses, section under Chlorine (IV) Oxide; SodiumChlorite analysis, p. 156. The concentration was determined to be 1.36M. To prepare a 4.25 wt % solution (0.47 M), 200

mL were diluted to 580 mL.

Example 4 Toxicity

Jurkat T cells (cell line) were used to test nonspecific toxicity of achlorite formulation as described herein versus WF10. The formulationtested against WF10 was chlorite in water, with saline as a diluent. Theformulation was adjusted to a pH of about 7.4 using the method describedin Example 3, with sodium phosphate as buffer. The chlorite was atgreater than about 95% purity. Triplicate cultures of Jurkat T cellswere exposed to various concentrations of each chlorite formulation for24 hours at 37° C. The number of live cells for each concentrationtreatment was normalized to untreated cultures and plotted. Cellviability was measured by trypan blue exclusion. Trypan Blue is a dyethat is used to determine the viability of a cell. Living cells excludethe dye, whereas dead cells take up the dye. The blue stain is easilyvisible, and cells can be counted using a light microscope. The resultsare shown in FIG. 1. Based on the relative numbers of live cells, WF10treatment resulted in nonspecific toxicity at concentrations of 50 μMand higher, whereas TJ001 did not result in nonspecific toxicity untilconcentrations of 200 μM and higher.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1-82. (canceled)
 83. Pharmaceutically acceptable sodium chlorite insolid form containing an amount of chlorate ion, wherein said amount ofchlorate ion is less than about 1.5% by weight.
 84. Pharmaceuticallyacceptable sodium chlorite in solid form containing an amount of sulfateion, wherein said amount of sulfate ion is less than about 0.7% byweight.
 85. Pharmaceutically acceptable sodium chlorite in solid formcontaining an amount of chloride ion, wherein said amount of chlorideion is less than about 1.9% by weight.
 86. A method of purifying sodiumchlorite to yield pharmaceutically acceptable sodium chlorite accordingto claim 83 comprising (i) concentrating a sodium chlorite solution at atemperature between 60° C. to about 100° C., whereby impuritiesprecipitate from the solution; (ii) removing the precipitated impuritiesfrom the concentrated solution by filtration; (iii) inducingcrystallization of sodium chlorite from the concentrated solution bylowering the temperature to below about 0° C.; and (iv) harvesting theresulting sodium chlorite solids by filtration.
 87. A method ofpreparing a pharmaceutical formulation of sodium chlorite comprisingdissolving pharmaceutically acceptable sodium chlorite preparedaccording to claim 86 in water or an aqueous solvent suitable forintravenous administration.
 88. The method of claim 87, furthercomprising lowering the pH of the formulation by addition of a pHadjusting agent.
 89. The method of claim 88, wherein said lowering ofthe pH of the formulation is performed without exposing the formulationto an acidic pH.
 90. The method of claim 88, wherein said lowering ofthe pH of the formulation is performed without exposing the sodiumchlorite in the formulation to high local acidity.